Tumor-promoting and cocarcinogenic agents are important factors in environmental carcinogenesis. Yet, few studies have been carried out on structure-biological activity relationships of these agents, their metabolism in vivo, or mode of action. The proposed study will focus on anthralin which is a potent mouse-skin tumor-promoting agent and cocarcinogen. This compound, 1,8-dihydroxy-9-anthrone, undergoes intramolecular hydrogen bonding, and from its structure, is expected to form chelate or related metal complexes with a variety of biologically important metals. The studies to be undertaken under this application will focus on the synthesis of a series of analogs of anthralin and the determination of their tumor-promoting and cocarcinogenic activity on mouse skin. The parent compound and its analogs will be examined for in vitro complex formation with biologically important metals including calcium, magnesium, zinc and manganese. Copper complexes will also be examined in model studies. Hydrogen bonding studies will be carried out by theoretical evaluations as well as by infrared and NMR spectroscopy. C14- and H3-labelled anthralin will be synthesized for the study of its metabolism and tissue localization. The role of the inflammatory response in tumor-promotion will be examined by the use of agents which are inactive as tumor-promoters but which cause inflammatory reactions in mouse skin. A knowledge of the manner which tumor-promoters exert their oncogenic potential will contribute to understanding basic mechanisms of carcinogenesis and to the practical aspects of cancer prevention with respect to environmental tumor- promoting and cocarcinogenic agents.